The term adjuvant is used to designate an auxiliary agent which when administered jointly with an antigen increases the immunogenicity of the antigen or influences the quality of the immune response. Adjuvants are administered with the intention of improving the immunogenicity of an antigen, i.e. to increase antibody formation and/or to induce a stronger cell mediated immune response to the antigen.
Customary adjuvants are aluminum compounds, lipid-containing compounds as well as inactivated Mycobacteria. Freund's adjuvant, a water-in-oil emulsion, is one of the most efficient adjuvants. This adjuvant is especially effective when Mycobacteria are suspended together with the antigen in the emulsion (Freund's complete adjuvant). However, a disadvantage of this adjuvant with use in humans is the possible appearance of chronic inflammation. On the other hand, emulsions without Mycobacteria (Freund's incomplete adjuvant) lead to lesser side-effects and are therefore already applied in humans.
A further group of adjuvants constitute suspensions of mineral salts to which the corresponding antigen is adsorbed. The customary adjuvants of this type are compounds of aluminum such as aluminum hydroxide, aluminum phosphate or aluminum sulfate.
Certain lymphokines also show adjuvant activity. For example, an increase in the immune response against malaria antigen by recombinant human interleukin-2 adsorbed to aluminum was reported by Good et al., J. Immunol. 141, 972-977, 1988. Nakamura et al., Nature 307, 381-382, 1984, demonstrated a 2- to 5-fold increase in antibody production against different antigens by gamma-interferon.
Aside from the immunological mode of action, the pharmacokinetics and/or biodegradability of the respective material are a further criteria for its suitability as an adjuvant. In general, materials which are subjected to metabolism in the organism are generally less toxic and tolerated very well locally. This is especially true for iron, which has been found to be the most important trace element in human and animal organisms. This iron commonly exists in the form of iron salts which are present in ionic form after intake into the body and can be reabsorbed very well.
Aside from the above mentioned adjuvants, further materials with adjuvant properties are also known. In EP-B-0363 835, a zinc hydroxide gel or iron hydroxide gel is described for adjuving an antigen solution. The adjuvant solution contains, for example, 1-45% (v/v) iron hydroxide gel and optionally lecithin. Starting from an FeCl.sub.3 solution after sterile filtration, the adjuvant is obtained as a precipitate by adding NaOH or KOH up to a pH value of 6.0 to 7.8. The precipitated iron hydroxide gel is optionally homogenized by Ultra-Turrax.RTM.R treatment. However, a colloidal iron III hydroxide does not result from this treatment; instead, the substance is still present as a gel, as shown in comparative experiment 1. The iron hydroxide gel produced in this manner predominantly induces a humoral immune response. In addition, it is shown in comparative experiment 2 that the gel obtained according to EP-363 835 behaves differently in its protein adsorption than the colloidal solution according to the invention which is capable of binding a distinctly larger amount of protein.
U.S. Pat No. 4,452,773 describes ferromagnetic particles of Fe.sub.3 O.sub.4 which are coated with water soluble polysaccharides and are of colloidal size. The particles have a diameter between 100 and 700 .ANG., possess a magnetic moment, are mono-dispersable and are stable against aggregation and degradation under physiological conditions. Based on their ferromagnetic properties, they are suitable for the labeling of cells or other biological materials. As a result of their different design and different properties these particles serve a completely different purpose and are especially used for labeling of biomolecules.
In WO-A-94 15 635, a pharmaceutical composition is described which comprises a particulate protein complex of a particulate component bound to a non-replicating protein antigen. The particulate component can, among other things, be a metal, preferably a metal from the transition elements scandium to copper or a corresponding metal oxide, especially iron oxide. The iron (III) oxide is present as a magnetic .gamma.-oxide.
The adjuvants based on iron described in the prior art have the disadvantage that, on the one hand, the surfaces of the iron compounds are as a whole relatively small, which implies less adsorption of the antigen and, on the other hand, these compounds are poorly or less rapidly adsorbed by the organism.